Tuberous Sclerosis (TS) is an autosomal dominant disorder that is characterized by the development of benign and malignant tumors of the brain, kidney, lung, and skin. TS is characterized by mutations or deletions in one of two genes, either hamartin (tsc1) or tuberin (tsc2). Furthermore, TS is associated with neuro-developmental complications, including autism and seizures, leading to significant morbidity. Although there is no known strict genotype-phenotype relationship with TS, the disease is more severe in patients with tsc2 mutations. Loss of heterozygosity, in which the unaffected allele is deleted, is necessary for the development of certain neoplastic features of TS, including renal angiomyolipomas, lymphangiomyomatosis, and skin lesions.
TS is associated with a number of complex signaling pathways. Tsc2 mutations often involve regions implicated in controlling rheb, although other signaling pathways have been implicated in TS-related neoplasia, including mTORC1, notch, p42/44 MAP kinase, NFkB, and Akt. The use of sirolimus as a therapy for TS has been based on the upregulation of mTORC1 in the neoplasms of TS patients. Although sirolimus resulted in a partial regression of kidney, lung and skin lesions, there was not a complete disappearance of tumors. See, e.g., Franz, D. N. et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006 March; 59(3):490-8. Furthermore, tumor regrowth was observed upon cessation of sirolimus therapy. Bissler, J J. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan. 10; 358(2):140-51. These clinical observations indicate that other signaling pathways may be active in TS-related tumors.